Aminoglycosides are bactericidal antibiotics derived from bacteria of the order Actinomycetales, more specifically from the genus Streptomyces or Micromonospora. They are polycationic compounds containing an aminocyclitol with cyclic amino-sugars attached by glycosidic linkages. Generally, the sulfate salts are used. The aminoglycosides have similar toxicological features, with ototoxicity as the major limitation to their use. Other common adverse effects are nephrotoxicity, neuromuscular blocking activity, and allergy, including cross-reactivity. They have a similar antimicrobial spectrum and appear to act by interfering with bacterial protein synthesis, possibly by binding irreversibly to the 30S and to some extent the 50S portions of the bacterial ribosome. They are most active against Gram-negative rods. Gram-negative species including Brucella, Clymmatobacterium, Campylobacter, Citrobacter, Escherichia, Enterobacter, Klebsiella, Proteus, Providencia, Pseudomonas, Serratia, Vibrio and Yersinia have been reported to be sensitive to aminoglycosides. Furthermore, Gram-positive strains such as Staphylococcus aureus are highly sensitive to aminoglycosides such as gentamicin sulfate. Also some actinomycetes and mycoplasmas would be sensitive to aminoglycosides. Bacterial resistance is usually associated with the plasmid-mediated production of inactivating enzymes. Based on their activity spectrum, they are used to treat infections such as biliary-tract infections, brucellosis, cat scratch disease, cystic fibrosis, endocarditis, endometritis, gastro-enteritis, granuloma inguinale, listeriosis, meningitis, otitis externa, otitis media, pelvic inflammatory disease, peritonitis, plague, pneumonia, septicaemia, skin infections and urinary-tract infections, as well as in the prophylaxis of surgical infection and the treatment of immunocompromised patients and those in intensive care. The aminoglycosides have a postantibiotic effect, where the antibacterial activity persists after concentrations have dropped below minimum inhibitory concentrations (Martindale—The complete drug reference, 1999, thirty-second edition, ed. K. Parfitt, Pharmaceutical Press).
Arbekacin is an aminoglycoside derived from dibekacin. It is used as arbekacin sulfate in the treatment of serious infections due to methicillin-resistant Staphylococcus aureus (Martindale—The complete drug reference, 1999, thirty-second edition, ed. K. Parfitt, Pharmaceutical Press). Arbekacin was first described in JP 56051499 A and JP 58134099 A and is marketed as an arbekacin sulfate solution for parenteral application.
Little of the aminoglycosides is absorbed from the gastro-intestinal tract, and aminoglycosides have preferably been administered intravenously. However, there is a high potential for severe systemic side effects (such as ototoxicity and nephrotoxicity) due to the narrow margin between therapeutic and toxic doses. Additionally, for treatment of respiratory infections, relatively high parenteral doses must be administered as aminoglycosides diffuse poorly across lipid membranes and into bronchial secretions. This may impair their efficacy as often only sub-inhibitory aminoglycoside concentrations are present at the site of infection. Several approaches to avoid toxicity and increase the efficacy of aminoglycosides have been proposed (Ratjen et al., “Aminoglycoside therapy against Pseudomonas aeruginosa in cystic fibrosis: A review”, Journal of Cystic Fibrosis 8 (2009) 361-369). For example, U.S. Pat. No. 6,221,388 describes liposome-encapsulated aminoglycoside formulations and U.S. Pat. No. 5,508,269 describes direct administration of tobramycin to the infected respiratory tract.
Aerosolisation of for example gentamicin, tobramycin and amikacin has been evaluated and applied to raise concentrations in the respiratory tract while avoiding toxicity. Examples of aminoglycoside formulations for inhalation are TOBI® (U.S. Pat. No. 5,508,269), Bramitob® (U.S. Pat. No. 6,987,094) and Arikace® (U.S. Pat. No. 7,718,189). However, some of these formulations require very long nebulisation times, which reduce patient compliance.